Osteoporosis is a major public health threat. Currently, osteoporosis is present in an estimated 44 million men and women aged 50 and older, which represent 55 percent of the population in that age group in the USA. In addition to the enormous medical costs, this condition leads to a substantial increase in mortality. A new approach for the treatment of osteoporosis and other musculoskeletal diseases is proposed a targeted drug delivery system employing bone targeted;water-soluble polymer conjugates as carriers for the anabolic agent, prostaglandin E1. Previous experiments have demonstrated that D-Asp8-targeted conjugates are preferentially incorporated onto bone resorption surfaces. This offers a unique opportunity to target drugs to sites of active bone resorption. Another encouraging result was the observation that increases in bone formation could be sustained for at least a month following a single injection of the conjugate. The main aim of the proposed research is to design novel, effective conjugates for the treatment of osteoporosis. We designed new, biodegradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. An important design characteristic is the insertion of degradable bonds into the polymer main chain (backbone). Consequently, a higher molecular weight than with nondegradable carriers may be used, resulting in long circulation times and enhanced accumulation in bone due to leaky vasculature and increased number of targeting moieties per chain. Main features of the new design are as follows: a) The new biodegradable HPMA-based polymeric carrier will be composed of short telechelic HPMA copolymer segments, containing PGE1 and targeting moieties, prepared by RAFT (reversible addition-fragmentation chain transfer) polymerization using an azido-functionalized RAFT chain transfer agent. These segments will be extended into high molecular weight (long-circulating) carriers by a highly efficient click chemistry reaction with enzymatically degradable (acetylene functionalized) oligopeptides;b) The targeting D-Asp8 group will be bound to the polymer backbone via a cathepsin K sensitive spacer;c) PGE1 will be bound to the polymer backbone via an ether bond;it will be connected to the carrier via an 1,6-elimination group and a cathepsin K sensitive spacer. The previously used ester bond was stable in humans, but susceptible to hydrolysis in rat and mouse plasma, which complicated the optimization of the conjugate. The new design will avoid these difficulties. To optimize the therapeutic protocol a dose escalation study, a time sequence study, and a multiple dose study will be performed. Numerous analyses will be performed to determine the effect of the conjugates on various bone indices, namely bone mineral density, bone mineral content, bone biomechanical, biomorphometric, and histomorphometric properties. The concept of (main chain) biodegradable HPMA copolymer drug carriers targeted to bone resorption sites is a new paradigm for the design of efficient drugs for the treatment of musculoskeletal diseases. PUBLIC HEALTH RELEVANCE The proposal addresses one of the important problems of osteoporosis treatment delivery of (anabolic) drugs to sites of bone resorption. The advantages of the proposed drug delivery systems are: selective adsorption to the tissues in bone with higher rates of bone turnover, localization of the anabolic agent (prostaglandin E1) in skeletal sites where bone formation would be beneficial, the reduction of side-effects resulting from systemic administration of free drugs, and applicability of design principles to the delivery of other drugs.